Hypertension is one of the strongest predictors of cardiovascular disease (CVD) in women. Despite extensive knowledge of the etiology of hypertension and the availability of effective treatments, prevalence remains high. There is a substantial need for novel strategies to identify premenopausal women at high risk for hypertension who would benefit from early intervention to reduce their long term risk of CVD. Up to 20% of premenopausal women meet clinical criteria for premenstrual syndrome (PMS), a disorder characterized by moderate to severe luteal phase symptoms that substantially interfere with normal life activities and interpersonal relationships. The pathophysiology of PMS is complex, and factors including dysfunction of the renin-angiotensin-aldosterone system and vitamin D insufficiency likely contribute. Importantly, these factors have also been implicated in the etiology of hypertension. Thus, moderate to severe PMS may be predictive of increased risk of hypertension later in life, and may serve as an early sentinel of CVD risk. The proposed project will extend work completed during the Principal Investigator's current career development award (K01MH07624) to explore the relation of PMS with hypertension and blood pressure in two populations of women. First, we will determine prospectively if PMS occurring in the middle reproductive years is associated with subsequent risk of hypertension and changes in blood pressure over time. We have developed a prospective study of PMS nested within the Nurses' Health Study II (NHS2) cohort; to our knowledge, this is the only prospective epidemiologic study of women with PMS in existence. The NHS2 PMS Sub-Study includes 1257 women meeting established criteria for moderate to severe PMS and a comparison group of 2463 women without PMS. As of 2013, participants will have been followed for 24 years for incident hypertension and changes in blood pressure, and women with PMS will have been observed for up to 20 years following their PMS diagnosis. Second, we will determine if common PMS treatments and dietary and behavioral factors modify the association of PMS and blood pressure, and thus may provide opportunities for women experiencing PMS to reduce their risk of hypertension and CVD. Finally, using data from a second study of young adult women (n=375), we will determine if differences in blood pressure are already evident in women experiencing PMS in their late teens and early 20's. Data from both studies have already been collected, thus providing a cost- effective way to address these novel and important questions. IMPACT: This life course study will be the first to evaluate whether moderate to severe PMS may serve as an early sentinel of long-term health outcomes. It may help identify a population of women at high risk for hypertension who would benefit from increased screening and early intervention. Furthermore, it may lead to clinical trials of novels strategies for treating PMS, no only to reduce morbidity and improve quality of life in women with the disorder, but also to reduce their long-term risk of cardiovascular disease. PUBLIC HEALTH RELEVANCE: Hypertension is among the strongest predictors of cardiovascular disease in women, but despite extensive knowledge of its causes and the availability of effective treatments, the prevalence of hypertension remains high. The proposed project will determine if women experiencing moderate to severe premenstrual syndrome (PMS) are at higher risk of subsequently developing hypertension, and thus whether PMS may be an early sentinel of cardiovascular disease risk. This unique study will be the first prospective assessment of the relation of PMS and blood pressure, and may help identify women who would benefit from increased screening and early intervention to prevent hypertension and lower risk of cardiovascular disease.